Abstract Substance Use Disorders (SUDs) present a serious public health problem with significant health-related morbidity, and no FDA-approved treatments target cocaine use disorder (CUD) or co-occurring substance abuse. A major obstacle to SUD treatment are the high relapse rates, and high drug craving and reduced cognitive flexibility, particularly in stress, drug cue and challenge contexts, are target processes that contribute to such high relapse rates. Furthermore, CUD women show greater drug craving and poor cognitive flexibility during stress and drug cue challenge contexts, and preliminary data show that treatment with the alpha-2 adrenergic agonist, Guanfacine (GUA) at 3mg/s day versus placebo (PBO) reverses these effects in CUD women but not men. Preliminary data also show that GUA 3 mg/day vs. PBO led to higher drug-negative urines in an 8- week outpatient setting in CUD women than men. On the basis of this previous development work, we propose a 3- year R01 pilot clinical and laboratory outcome study to test the overall hypothesis that GUA (3mg/day) will reduce target drug craving and improve cognitive flexibility processes in CUD women, and that such targeted engagement will result in lower cocaine and other drug use outcomes in women with CUD. One hundred treatment seeking CUD women will be randomly assigned to GUA (3 mg/day) vs Placebo (PBO) over a 10-week clinical trial across 2 sites (N=50 per site), and will also be assessed in a pre-treatment and week 9 laboratory challenge test with exposure to stress and drug cue provocation. The primary target engagement outcome will be reduction in drug craving and improved cognitive flexibility and the primary target validation outcome will be reduced cocaine use as measured by percent negative drug urines and last three weeks of abstinence. The following aims will be addressed. Aim #1 - Target Engagement: To examine whether GUA will reduce drug craving and improve cognitive flexibility in laboratory challenge and in clinical assessments over the 10-week period. Aim #2: Target Validation: To evaluate whether GUA vs PBO effects on drug craving and cognitive flexibility significantly predicts CUD clinical outcomes in the 10-week trial. Aim #3: Data Replication and Scalability: To replicate target engagement and validation outcomes across two sites (Yale and SUNY-Stony Brook) and inform scalability for larger clinical trials. Exploratory Aim 1: To explore GUA?s role in mediating the relationship between target drug craving and cognitive flexibility processes and cocaine use and other drug use outcomes. Exploratory Aim 2: To explore the role of co-morbid psychiatric symptoms (mood, anxiety and PTSD) in moderating the proposed target engagement and validation processes. Acknowledging the heterogeneity in CUD and significant sex differences, this project utilizes an experimental therapeutics approach to further develop and test whether GUA?s targeted effects on drug craving and cognitive flexibility impacts substance use clinical outcomes, thereby providing critical data on whether such a personalized medicine approach to the development of GUA in the treatment of women with CUD is warranted.